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Article ; Online: Drug Interactions in Lenacapavir-Based Long-Acting Antiviral Combinations.

Cilento, Maria E / Ong, Yee Tsuey / Tedbury, Philip R / Sarafianos, Stefan G

2022 Volume 14, Issue 6

Abstract: Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients' quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase ... ...

Abstract	Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients' quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens.
MeSH term(s)	Anti-HIV Agents/therapeutic use ; Drug Combinations ; Drug Interactions ; HIV Infections/drug therapy ; Humans ; Quality of Life ; Reverse Transcriptase Inhibitors/therapeutic use ; Rilpivirine/pharmacology ; Rilpivirine/therapeutic use
Chemical Substances	Anti-HIV Agents ; Drug Combinations ; Reverse Transcriptase Inhibitors ; cabotegravir, rilpivirine drug combination ; Rilpivirine (FI96A8X663)
Language	English
Publishing date	2022-05-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14061202
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Drug Interactions in Lenacapavir-Based Long-Acting Antiviral Combinations

Cilento, Maria E. / Ong, Yee Tsuey / Tedbury, Philip R. / Sarafianos, Stefan G.

Viruses. 2022 May 31, v. 14, no. 6

2022

Abstract: Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase ... ...

Abstract	Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens.
Keywords	RNA-directed DNA polymerase ; antagonism ; antiretroviral agents ; cell lines ; dose response ; drug interactions ; integrases ; nucleosides ; quality of life
Language	English
Dates of publication	2022-0531
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14061202
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Article ; Online: HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection.

Yapo, Vincent / Majumder, Kinjal / Tedbury, Philip R / Wen, Xin / Ong, Yee T / Johnson, Marc C / Sarafianos, Stefan G

Journal of virology

2023 Volume 97, Issue 12, Page(s) e0187022

Abstract: Importance: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first ... ...

Abstract	Importance: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.
MeSH term(s)	Humans ; Coinfection/immunology ; Coinfection/virology ; HIV Long Terminal Repeat/genetics ; HIV-1/genetics ; HIV-1/immunology ; HIV-2/genetics ; HIV-2/immunology ; HIV-2/metabolism ; RNA, Viral/genetics ; tat Gene Products, Human Immunodeficiency Virus/metabolism ; Gene Expression Regulation, Viral ; Interferons/immunology ; Promoter Regions, Genetic/genetics ; Binding, Competitive ; RNA Polymerase II/metabolism ; Transcription, Genetic
Chemical Substances	RNA, Viral ; tat Gene Products, Human Immunodeficiency Virus ; Interferons (9008-11-1) ; tat peptide (17-25), Human immunodeficiency virus 1 ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01870-22
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Article ; Online: Exposing HIV's weaknesses.

Tedbury, Philip R / Sarafianos, Stefan G

The Journal of biological chemistry

2017 Volume 292, Issue 14, Page(s) 6027–6028

Abstract: The viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion ... ...

Abstract	The viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion machinery. This work advances our understanding of host-virus interactions and provides a compelling case for considering the host immune system in studies of restriction factor mechanisms.
MeSH term(s)	Antibodies, Neutralizing/immunology ; HIV Antibodies/immunology ; HIV Infections/immunology ; HIV-1/immunology ; Humans ; Membrane Proteins/immunology ; Protein Folding ; Virus Internalization
Chemical Substances	Antibodies, Neutralizing ; HIV Antibodies ; Membrane Proteins ; SERINC5 protein, human
Language	English
Publishing date	2017-04-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.H117.777714
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Article: HIV-1 gag: an emerging target for antiretroviral therapy.

Tedbury, Philip R / Freed, Eric O

Current topics in microbiology and immunology

2015 Volume 389, Page(s) 171–201

Abstract: The advances made in the treatment of HIV-1 infection represent a major success of modern biomedical research, prolonging healthy life and reducing virus transmission. There remain, however, many challenges relating primarily to side effects of long-term ...

Abstract	The advances made in the treatment of HIV-1 infection represent a major success of modern biomedical research, prolonging healthy life and reducing virus transmission. There remain, however, many challenges relating primarily to side effects of long-term therapy and the ever-present danger of the emergence of drug-resistant strains. To counter these threats, there is a continuing need for new and better drugs, ideally targeting multiple independent steps in the HIV-1 replication cycle. The most successful current drugs target the viral enzymes: protease (PR), reverse transcriptase (RT), and integrase (IN). In this review, we outline the advances made in targeting the Gag protein and its mature products, particularly capsid and nucleocapsid, and highlight possible targets for future pharmacological intervention.
MeSH term(s)	Acquired Immunodeficiency Syndrome/drug therapy ; Anti-HIV Agents/pharmacology ; Capsid Proteins/antagonists & inhibitors ; Gene Products, gag/antagonists & inhibitors ; HIV-1 ; Humans ; Nucleocapsid/antagonists & inhibitors ; Viral Matrix Proteins/antagonists & inhibitors ; Virus Replication/drug effects
Chemical Substances	Anti-HIV Agents ; Capsid Proteins ; Gene Products, gag ; Viral Matrix Proteins
Language	English
Publishing date	2015-03-03
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/82_2015_436
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Article: Marine Natural Products as Leads against SARS-CoV-2 Infection

Chhetri, Bhuwan Khatri / Tedbury, Philip R. / Sweeney-Jones, Anne Marie / Mani, Luke / Soapi, Katy / Manfredi, Candela / Sorscher, Eric / Sarafianos, Stefan G. / Kubanek, Julia

Journal of natural products. 2022 Mar. 15, v. 85, no. 3

2022

Abstract: Since early 2020, disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, causing millions of infections and deaths worldwide. Despite rapid deployment of effective vaccines, it is apparent that ... ...

Abstract	Since early 2020, disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, causing millions of infections and deaths worldwide. Despite rapid deployment of effective vaccines, it is apparent that the global community lacks multipronged interventions to combat viral infection and disease. A major limitation is the paucity of antiviral drug options representing diverse molecular scaffolds and mechanisms of action. Here we report the antiviral activities of three distinct marine natural products─homofascaplysin A (1), (+)-aureol (2), and bromophycolide A (3)─evidenced by their ability to inhibit SARS-CoV-2 replication at concentrations that are nontoxic toward human airway epithelial cells. These compounds stand as promising candidates for further exploration toward the discovery of novel drug leads against SARS-CoV-2.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; antiviral agents ; epithelium ; humans ; pandemic
Language	English
Dates of publication	2022-0315
Size	p. 657-665.
Publishing place	American Chemical Society and American Society of Pharmacognosy
Document type	Article
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.2c00015
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The cytoplasmic tail of retroviral envelope glycoproteins.

Tedbury, Philip R / Freed, Eric O

Progress in molecular biology and translational science

2014 Volume 129, Page(s) 253–284

Abstract: Retroviruses comprise a large, diverse group that infects a broad range of host organisms. Pathogenicity varies widely; the human immunodeficiency virus is the causative agent of acquired immunodeficiency syndrome, one of the world's leading infectious ... ...

Abstract	Retroviruses comprise a large, diverse group that infects a broad range of host organisms. Pathogenicity varies widely; the human immunodeficiency virus is the causative agent of acquired immunodeficiency syndrome, one of the world's leading infectious causes of death, while many nonhuman retroviruses cause cancer in the host. Retroviruses have been studied intensively, and great strides have been made in understanding aspects of retroviral biology. While the principal functions of the viral structural proteins are well understood, there remain many incompletely characterized domains. One of these is the cytoplasmic tail (CT) of the envelope glycoprotein. Several functions of the CT are highly conserved, whereas other properties are unique to a specific retrovirus. For example, the lentiviruses encode envelope glycoproteins with particularly large cytoplasmic domains. The functions of the long lentiviral envelope CT are still being deciphered. The reported functions of retroviral envelope CTs are discussed in this chapter.
MeSH term(s)	Animals ; Cytoplasm/metabolism ; Glycoproteins/biosynthesis ; Glycoproteins/chemistry ; Humans ; Models, Biological ; Retroviridae/metabolism ; Viral Envelope Proteins/biosynthesis ; Viral Envelope Proteins/chemistry ; Virus Assembly
Chemical Substances	Glycoproteins ; Viral Envelope Proteins
Language	English
Publishing date	2014-12-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	2471995-X
ISSN	1878-0814 ; 0079-6603 ; 1877-1173
ISSN (online)	1878-0814
ISSN	0079-6603 ; 1877-1173
DOI	10.1016/bs.pmbts.2014.10.009
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Article ; Online: The role of matrix in HIV-1 envelope glycoprotein incorporation.

Tedbury, Philip R / Freed, Eric O

Trends in microbiology

2014 Volume 22, Issue 7, Page(s) 372–378

Abstract: Incorporation of the viral envelope (Env) glycoprotein is a critical requirement for the production of infectious HIV-1 particles. It has long been appreciated that the matrix (MA) domain of the Gag polyprotein and the cytoplasmic tail of Env are central ...

Abstract	Incorporation of the viral envelope (Env) glycoprotein is a critical requirement for the production of infectious HIV-1 particles. It has long been appreciated that the matrix (MA) domain of the Gag polyprotein and the cytoplasmic tail of Env are central players in the process of Env incorporation, but the precise mechanisms have been elusive. Several recent developments have thrown light on the contributions of both proteins, prompting a re-evaluation of the role of MA during Env incorporation. The two domains appear to play distinct but complementary roles, with the cytoplasmic tail of Env responsible for directing Env to the site of assembly and the matrix domain accommodating the cytoplasmic tail of Env in the Gag lattice.
MeSH term(s)	HIV Antigens/metabolism ; HIV-1/physiology ; Protein Binding ; Virus Assembly ; env Gene Products, Human Immunodeficiency Virus/metabolism ; gag Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	HIV Antigens ; env Gene Products, Human Immunodeficiency Virus ; gag Gene Products, Human Immunodeficiency Virus ; p17 protein, Human Immunodeficiency Virus Type 1
Language	English
Publishing date	2014-06-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2014.04.012
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Article: Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies.

Lan, Shuiyun / Neilsen, Grace / Slack, Ryan L / Cantara, William A / Castaner, Andres Emanuelli / Lorson, Zachary C / Lulkin, Nicole / Zhang, Huanchun / Lee, Jasper / Cilento, Maria E / Tedbury, Philip R / Sarafianos, Stefan G

bioRxiv : the preprint server for biology

2023

Abstract: The antiviral component of Paxlovid, nirmatrelvir (NIR), forms a covalent bond with Cys145 of SARS-CoV-2 nsp5. To explore NIR resistance we designed mutations to impair binding of NIR over substrate. Using 12 Omicron (BA.1) and WA.1 SARS-CoV-2 replicons, ...

Abstract	The antiviral component of Paxlovid, nirmatrelvir (NIR), forms a covalent bond with Cys145 of SARS-CoV-2 nsp5. To explore NIR resistance we designed mutations to impair binding of NIR over substrate. Using 12 Omicron (BA.1) and WA.1 SARS-CoV-2 replicons, cell-based complementation and enzymatic assays, we showed that in both strains, E166V imparted high NIR resistance (∼55-fold), with major decrease in WA1 replicon fitness (∼20-fold), but not BA.1 (∼2-fold). WA1 replicon fitness was restored by L50F. These differences may contribute to a potentially lower barrier to resistance in Omicron than WA1. E166V is rare in untreated patients, albeit more prevalent in paxlovid-treated EPIC-HR clinical trial patients. Importantly, NIR-resistant replicons with E166V or E166V/L50F remained susceptible to a) the flexible GC376, and b) PF-00835231, which forms additional interactions. Molecular dynamics simulations show steric clashes between the rigid and bulky NIR t-butyl and β-branched V166 distancing the NIR warhead from its Cys145 target. In contrast, GC376, through "wiggling and jiggling" accommodates V166 and still covalently binds Cys145. PF-00835231 uses its strategically positioned methoxy-indole to form a β-sheet and overcome E166V. Drug design based on strategic flexibility and main chain-targeting may help develop second-generation nsp5-targeting antivirals efficient against NIR-resistant viruses.
Language	English
Publishing date	2023-01-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.12.31.522389
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Article ; Online: Mechanisms of Action of the Host-Targeting Agent Cyclosporin A and Direct-Acting Antiviral Agents against Hepatitis C Virus.

Liu, Dandan / Ndongwe, Tanya P / Ji, Juan / Huber, Andrew D / Michailidis, Eleftherios / Rice, Charles M / Ralston, Robert / Tedbury, Philip R / Sarafianos, Stefan G

Viruses

2023 Volume 15, Issue 4

Abstract: Several direct-acting antivirals (DAAs) are available, providing interferon-free strategies for a hepatitis C cure. In contrast to DAAs, host-targeting agents (HTAs) interfere with host cellular factors that are essential in the viral replication cycle; ... ...

Abstract	Several direct-acting antivirals (DAAs) are available, providing interferon-free strategies for a hepatitis C cure. In contrast to DAAs, host-targeting agents (HTAs) interfere with host cellular factors that are essential in the viral replication cycle; as host genes, they are less likely to rapidly mutate under drug pressure, thus potentially exhibiting a high barrier to resistance, in addition to distinct mechanisms of action. We compared the effects of cyclosporin A (CsA), a HTA that targets cyclophilin A (CypA), to DAAs, including inhibitors of nonstructural protein 5A (NS5A), NS3/4A, and NS5B, in Huh7.5.1 cells. Our data show that CsA suppressed HCV infection as rapidly as the fastest-acting DAAs. CsA and inhibitors of NS5A and NS3/4A, but not of NS5B, suppressed the production and release of infectious HCV particles. Intriguingly, while CsA rapidly suppressed infectious extracellular virus levels, it had no significant effect on the intracellular infectious virus, suggesting that, unlike the DAAs tested here, it may block a post-assembly step in the viral replication cycle. Hence, our findings shed light on the biological processes involved in HCV replication and the role of CypA.
MeSH term(s)	Humans ; Hepacivirus/genetics ; Antiviral Agents/therapeutic use ; Cyclosporine/pharmacology ; Cyclosporine/therapeutic use ; Hepatitis C, Chronic/drug therapy ; Viral Nonstructural Proteins/genetics ; Hepatitis C/drug therapy
Chemical Substances	Antiviral Agents ; Cyclosporine (83HN0GTJ6D) ; Viral Nonstructural Proteins
Language	English
Publishing date	2023-04-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15040981
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